文章：

伴卡非佐米诱导血栓性微血管病的多发性骨髓瘤患者中的替代补体途径突变

Mutations in the alternative complement pathway in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy

原文发布日期：2023-02-27

DOI: 10.1038/s41408-023-00802-0

类型: Article

开放获取: 是

英文摘要：

Thrombotic microangiopathy (TMA) has been reported to occur in multiple myeloma (MM) patients in association with treatment with carfilzomib, an irreversible proteasome inhibitor (PI). The hallmark of TMA is vascular endothelial damage leading to microangiopathic hemolytic anemia, platelet consumption, fibrin deposition and small-vessel thrombosis with resultant tissue ischemia. The molecular mechanisms underlying carfilzomib-associated TMA are not known. Germline mutations in the complement alternative pathway have been recently shown to portend increased risk for the development of atypical hemolytic uremic syndrome (aHUS) and TMA in the setting of allogeneic stem cell transplant in pediatric patients. We hypothesized that germline mutations in the complement alternative pathway may similarly predispose MM patients to carfilzomib-associated TMA. We identified 10 MM patients with a clinical diagnosis of TMA in the context of carfilzomib treatment and assessed for the presence of germline mutations in the complement alternative pathway. Ten, matched MM patients exposed to carfilzomib but without clinical TMA were used as negative controls. We identified a frequency of deletions in the complement Factor H genes 3 and 1 (delCFHR3-CFHR1) and genes 1 and 4 (delCFHR1-CFHR4) in MM patients with carfilzomib-associated TMA that was higher as compared to the general population and matched controls. Our data suggest that complement alternative pathway dysregulation may confer susceptibility to vascular endothelial injury in MM patients and predispose to development of carfilzomib-associated TMA. Larger, retrospective studies are needed to evaluate whether screening for complement mutations may be indicated to properly counsel patients about TMA risk with carfilzomib use.
 

摘要翻译： 

血栓性微血管病（TMA）已被报道在多发性骨髓瘤（MM）患者中发生，并与不可逆蛋白酶体抑制剂（PI）卡非佐米治疗相关。TMA的典型特征是血管内皮损伤，导致微血管病性溶血性贫血、血小板消耗、纤维蛋白沉积及小血管血栓形成，进而引起组织缺血。目前卡非佐米相关TMA的分子机制尚未明确。近期研究显示，补体旁路途径的胚系突变可能增加儿童患者异基因干细胞移植后发生非典型溶血性尿毒综合征（aHUS）和TMA的风险。我们推测，补体旁路途径的胚系突变可能同样使MM患者易发生卡非佐米相关TMA。我们鉴定了10例在卡非佐米治疗期间临床诊断为TMA的MM患者，并评估其补体旁路途径是否存在胚系突变。另选取10例接受卡非佐米治疗但未发生临床TMA的匹配MM患者作为阴性对照。我们发现，与普通人群及匹配对照组相比，卡非佐米相关TMA的MM患者中补体因子H基因3和1（delCFHR3-CFHR1）以及基因1和4（delCFHR1-CFHR4）缺失的发生频率更高。我们的数据表明，补体旁路途径失调可能增加MM患者血管内皮损伤的易感性，并促使卡非佐米相关TMA的发生。未来需要更大规模的回顾性研究来评估补体突变筛查是否有助于为患者提供卡非佐米使用相关TMA风险的合理指导。

原文链接：

Mutations in the alternative complement pathway in multiple myeloma patients with carfilzomib-induced thrombotic microangiopathy